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Treatment failure or relapse due to tumor escape caused by reduction in target antigen expression has become a challenge in the field of CART therapy. Target antigen density is closely related to the effectiveness of CART therapy, and reduced or lost target antigen expression limits the efficacy of CART therapy and hinders the durability of CAR T cells. Epigenetic drugs can regulate histones for molecular modifications to regulate the transcriptional, translational and post-translational modification processes of target agents, and we demonstrated for the first time the role in regulating CD22 expression and its effect on the efficacy of CD22 CART. In this paper, we found that Chidamide promoted the expression of CD22 on the surface of B-cell tumor cells in vitro and in vivo, and enhanced the function of CD22 CART. As for mechanisms, we demonstrated that Chidamide did not affect CD22 mRNA transcription, but significantly increased the expression of total CD22 protein, indicating that Chidamide may upregulate cell surface CD22 expression by affecting the distribution of CD22 protein. In summary, our results suggest that Chidamide may enhance the efficacy of CD22 CART by inhibiting histone deacetylases to regulate post-transcriptional modifications that affect protein distribution to increase the expression of CD22 on the cell surface.

Phellodendri Chinese Cortex has long been used to treat hyperuricemia and gout. Berberine (BBR), its characteristic ingredient, has also been shown to be effective in alleviating monosodium urate crystals-triggered gout inflammation in vitro and in vivo . Dihydroberberine (DHB) is a hydrogenated derivative of BBR that showed improved in vivo efficacy on many metabolic disorders. However, its anti-hyperuricemia effect remains underexplored. In the present work, the hypouricemic and renoprotective effects of DHB on hyperuricemic mice were investigated. The hyperuricemic mice model was induced by intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) combined with intragastric administration of hypoxanthine (HX, 300 mg/kg) for 7 days. Different dosages of DHB (25, 50 mg/kg), BBR (50 mg/kg) or febuxostat (Feb, 5 mg/kg) were orally given to mice 1 h after modeling. The molecular docking results showed that DHB effectively inhibited xanthine oxidase (XOD) by binding with its active site. In vitro , DHB exhibited significant XOD inhibitory activity (IC 50 value, 34.37 μM). The in vivo results showed that DHB had obvious hypouricemic and renoprotective effects in hyperuricemic mice. It could not only lower the uric acid and XOD levels in serum, but also suppress the activities of XOD and adenosine deaminase (ADA) in the liver. Furthermore, DHB noticeably down-regulated the renal mRNA and protein expression of XOD. Besides, DHB remarkably and dose-dependently ameliorated renal damage, as evidenced by considerably reducing serum creatinine and blood urea nitrogen (BUN) levels, inflammatory cytokine (TNF-α, IL-1β, IL-6 and IL-18) levels and restoring kidney histological deteriorations. Further mechanistic investigation showed that DHB distinctly down-regulated renal mRNA and protein levels of URAT1, GLUT9, NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), caspase-1 and IL-1β. Our study revealed that DHB had outstanding hypouricemic and renoprotective effects via suppressing XOD, URAT1, GLUT9 and NLRP3 inflammasome activation in the kidney.

Chimeric antigen receptor (CAR) T-cell infusion (CTI) therapy has emerged as a breakthrough therapy in relapsed/refractory B-cell non-Hodgkin’s lymphoma (R/R B-NHL), but a substantial number of patients still suffer treatment failure. Data on disease history, subsequent salvage therapies, and outcomes of patients who face treatment failure after the first CTI (CTI1) have not been reported in detail or systematically studied. Here, a retrospective analysis was performed on a total of 61 R/R B-NHL patients in whom salvage therapies were adopted after CTI1 treatment failure, with their clinical characteristics, subsequent management and outcomes described in detail. The results suggested that second-time CTI (CTI2) used as salvage therapy after failure of CTI1 could achieve a better transient overall response rate (ORR) than other salvage treatments (non-CTI2) in only a minority of patients (8/27 vs. 2/34, P =0.014). Nevertheless, the non-CTI2 group showed better event-free survival (EFS) ( P = 0.007) and overall survival (OS) ( P = 0.048) than the CTI2 group, with a median follow-up of 6.7 months vs. 4.7 months. In addition, univariate and multivariate analyses showed that only the status of the tumor at disease onset was an independent risk factor for survival; salvage therapy after CTI1 treatment failure was not. The adverse effects of CTI2 treatment were generally similar to those of non-CTI2 treatment, but the infection-related mortality was considerably higher. In conclusion, the prognosis of patients who fail CTI1 therapy is very poor regardless of the subsequent salvage therapies, and clinicians should be cautious about adopting CTI2 treatment after failure of treatment with the CD19/22 cocktail CTI1 in R/R B-NHL. Large-scale prospective studies are warranted, and new strategies are urgently needed to prevent treatment failure and improve the survival of B-cell lymphoma patients in future.

Based on the transient-performance calculation model of a dual-spool mixed-flow turbofan engine, this article improves the dynamic algorithm of geometric adjustment mechanisms and establishes a transient-performance calculation model suitable for a three-stream adaptive cycle engine (three-stream ACE). Using this model, the transient characteristics of a three-stream ACE were analyzed. The results indicate that the delay in the area of the fan nozzle significantly reduces the surge margin of the front fan during deceleration, while the delay in the angle of the front-fan and aft-fan guide vanes significantly reduces the surge margin of the front fan during acceleration, therefore becoming a limitation of the transient performance of the engine. At the same time, to meet the demand for equal-thrust mode switching, this article also proposes a mode-switching control scheme that solves the problem of engine state oscillation during the mode-conversion process and achieves a smooth conversion with thrust fluctuations within 1%. The research results of this article can guide the optimization design of three-stream ACE transition-state control laws and the design of control system architecture, which has important engineering significance.

In response to the green development concept of the textile industry, this article describes the development of a biodegradable and eco-friendly raw starch sizing agent formulation. The sizing agent performance, sizing quality, biodegradation, weave efficiency, and production cost of the raw starch formulation in raw starch sizing process were compared with three other formulations. The results showed that the formulation prepared with raw starch achieved a lower viscosity and higher stability compared with the other three formulations. The raw starch sizing exhibited excellent moisture regain, moisture absorption performance and breaking strength, high enhancement rate and low elongation, high penetration, low coating, and abrasion resistance. The raw starch formulation was shown to be energy-saving and environmentally friendly, with higher weave efficiency and lower production costs. The BOD5/COD was 0.65, which means that the desizing wastewater is easy to degrade. Sizing agent cost was 17 to 61% lower and loom efficiency was 5% to 12% higher. This research provides a theoretical basis for promoting the usage of raw starch sizing in practical production, which contributes to green and eco-friendly processing.

Hawthorn leave flavonoids (HLF) are widely used as an herb or dietary supplements for cardio-cerebrovascular diseases. However, its gastrointestinal absorption behavior and mechanism have not been disclosed. In this study, gastrointestinal absorption and its regulation of 4’’- O -glucosylvitexin (GLV), 2’’- O -rhamnosylvitexin (RHV), vitexin (VIT), rutin (RUT) and hyperoside (HP) in HLF were investigated using in vitro, in situ and in vivo models. Apparent permeability coefficient ( P app ) of five flavonoids were (2.18 ± 0.15) ×10 −7 ~(3.83 ± 0.22) ×10 −7 cm·sec −1 across the Caco-2 cells. GLV, RHV, VIT and RUT demonstrated similar and poor absorption in rat stomach (absorption percentage per hour (A), (1.78 ± 0.14 ~ 5.69 ± 0.51)%·h −1 ) and small intestine (absorption rate ( , (0.012 ± 0.006 ~ 0.055 ± 0.003) h −1 ), extent (A, (1.28 ± 0.14 ~ 2.82 ± 0.19)% ·h −1 ) and potential ( P app , (0.31 ± 0.05 ~ 1.41 ± 0.08)×10 −7 cm·sec −1 )), while HP showed relatively better absorption ( P app , (2.55 ± 0.15 ~ 4.27 ± 0.36)×10 −7 cm·sec −1 ) in rat small intestine. Absorption of five flavonoids exhibited dose-dependence, pH-dependence and region-selectivity. Meanwhile, these flavonoids were excreted via intestine, secreted via bile and metabolized by intestinal microflora. Their absorption was significantly increased by absorption enhancers (cow bile salt and sodium dodecyl sulphate), transporter regulators (verapamil hydrochloride, digoxin and rifampicin). GLV and RHV exhibited enterohepatic circulation after oral administration of HLF. In conclusion, flavonoids in HLF were absorbed via passive diffusion accompanied with active transport, intestinal microflora metabolism, bile secretion and intestinal efflux. They belong to BCS class III (“like” drugs with high solubility and low permeability) and displayed poor oral bioavailability.

Hyperuricemia (HUA), a common metabolic disease, is treated as the second-largest metabolic disease after diabetes in China. Cortex Phellodendri (CP) is one of the most frequently used herbal medicines for treating gout or HUA. However, the mechanism underlying the anti-HUA effect of CP is still unrevealed. Hence, this study aimed to explore the pharmacological mechanism of CP against HUA using network pharmacology coupled with in vivo experimental validation. Active compounds and potential targets of CP, as well as the potential targets related to HUA, were retrieved from multiple open-source databases. The drug-disease overlapping targets were obtained by Venn diagram analysis and used to construct the herb-component-target (HCT), protein-protein-interaction (PPI), and component-target-pathway (CTP) networks. The functional enrichment analysis was also performed for further study. Furthermore, a HUA mouse model was induced by a combination of intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) and intragastric administration of hypoxanthine (HX, 300 mg/kg) daily for 10 days. Different dosages of CP (200, 400, and 800 mg/kg) were orally given to mice 1 h after modeling. The results showed that 12 bioactive compounds and 122 drug-disease overlapping targets were obtained by matching 415 CP-related targets and 679 HUA-related targets, and berberine was one of the most important compounds with the highest degree value. The core targets of CP for treating HUA were TP53, MAPK8, MAPK3, IL-6, c-Jun, AKT1, xanthine oxidase (XOD), and ATP-binding cassette subfamily G member 2 (ABCG2). The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results showed that the anti-HUA effect of CP mainly involved the pathways of inflammation and apoptosis, such as PI3K/Akt, TNF, MAPK, TLR, AMPK, NF-κB, and NLRP3 signaling pathways. In vivo animal experiment further confirmed the hypouricemic effect of CP in a HUA mouse model, as evidenced by significantly restored kidney histological deteriorations, and considerably decreased levels of serum uric acid (sUA), creatinine (Cre), blood urea nitrogen (BUN), and hepatic UA. Furthermore, the hypouricemic action of CP in vivo might be attributed to its suppression of XOD activity in the liver, rather than ABCG2 in the kidney. Real-time qPCR (RT-qPCR) and Western blot analysis also confirmed the key roles of the hub genes in CP against HUA. In conclusion, CP exhibited therapeutic effect against HUA via multi-compounds, multi-targets, and multi-pathways. It possessed anti-HUA and nephroprotective effects via suppressing XOD activity, and reversed the progression of renal injury by exerting anti-inflammatory and anti-apoptotic effects.

Background Exome sequencing (ES) is becoming more widely available in prenatal diagnosis. However, data on its clinical utility and integration into clinical management remain limited in practice. Herein, we report our experience implementing prenatal ES (pES) in a large cohort of fetuses with anomalies detected by ultrasonography using a hospital-based in-house multidisciplinary team (MDT) facilitated by a three-step genotype-driven followed by phenotype-driven analysis framework. Methods We performed pES in 1618 fetal cases with positive ultrasound findings but negative for karyotyping and chromosome microarray analysis between January 2014 and October 2021, including both retrospective ( n =565) and prospective ( n =1053) cohorts. The diagnostic efficiency and its correlation to organ systems involved, phenotypic spectrum, and the clinical impacts of pES results on pregnancy outcomes were analyzed. Results A genotype-driven followed by phenotype-driven three-step approach was carried out in all trio pES. Step 1, a genotype-driven analysis resulted in a diagnostic rate of 11.6% (187/1618). Step 2, a phenotype-driven comprehensive analysis yielded additional diagnostic findings for another 28 cases (1.7%; 28/1618). In the final step 3, data reanalyses based on new phenotypes and/or clinical requests found molecular diagnosis in 14 additional cases (0.9%; 14/1618). Altogether, 229 fetal cases (14.2%) received a molecular diagnosis, with a higher positive rate in the retrospective than the prospective cohort (17.3% vs. 12.4%, p <0.01). The diagnostic rates were highest in fetuses with skeletal anomalies (30.4%) and multiple organ involvements (25.9%), and lowest in fetuses with chest anomalies (0%). In addition, incidental and secondary findings with childhood-onset disorders were detected in 11 (0.7%) cases. Furthermore, we described the prenatal phenotypes for the first time for 27 gene-associated conditions (20.0%, 27/135) upon a systematic analysis of the diagnosed cases and expanded the phenotype spectrum for 26 (19.3%) genes where limited fetal phenotypic information was available. In the prospective cohort, the combined prenatal ultrasound and pES results had significantly impacted the clinical decisions (61.5%, 648/1053). Conclusions The genotype-driven approach could identify about 81.7% positive cases (11.6% of the total cohort) with the initial limited fetal phenotype information considered. The following two steps of phenotype-driven analysis and data reanalyses helped us find the causative variants in an additional 2.6% of the entire cohort (18.3% of all positive findings). Our extensive phenotype analysis on a large number of molecularly confirmed prenatal cases had greatly enriched our current knowledge on fetal phenotype-genotype correlation, which may guide more focused prenatal ultrasound in the future. This is by far the largest pES cohort study that combines a robust trio sequence data analysis, systematic phenotype-genotype correlation, and well-established MDT in a single prenatal clinical setting. This work underlines the value of pES as an essential component in prenatal diagnosis in guiding medical management and parental decision making.

Background Extramedullary disease usually implies a dismal outcome in relapsed/refractory multiple myeloma patients, and requires novel treatment approaches. We designed a trial using Selinexor, a nuclear export protein 1 inhibitor, together with anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell product CT103A to treat these patients, and describe the first two cases in this report. Methods Selinexor was administered with a novel two-step schedule in bridging therapy and in maintenance. The clinical responses and adverse events were recorded after CAR-T infusion and Selinexor administration. In vitro analysis of the influence of Selinexor on CAR-T cell function was performed using myeloma cell lines. Results After infusion, both patients achieved stringent complete remission (sCR), and were maintained in sCR at data-cutoff, with survival over 13 and 10 months, respectively. Neither immune effector cell-associated neurotoxicity syndrome nor over grade 2 cytokine release syndrome was observed. Meanwhile, the patients showed good tolerance to the combination. In addition, we demonstrated that low dose of Selinexor could upregulate the expression of BCMA on plasma cell lines and subsequently enhance the function of CAR-T cell in vitro. Conclusions The combination of Selinexor and CT103A exerts preliminary synergistic effect, and can be developed as a promising strategy for relapsed/refractory extramedullary myeloma.

Background B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy exhibits high response rates in patients with relapsed/refractory multiple myeloma (r/r MM). However, the specific factors that influence the response duration remain poorly understood. Methods This single-centre, retrospective observational study included 56 patients with r/r MM who received BCMA CAR-T therapy (equecabtagene autoleucel) at Tongji Hospital, China. We analysed response rates and long-term clinical outcomes and identified key factors contributing to the long-term efficacy of BCMA CAR-T therapy. Results At a median follow-up of 39.6 months, the overall response rate (ORR) was 96.4%. Among the patients, 96.4% (54 of 56) achieved minimal residual disease (MRD) negativity, whereas 80.4% (45 of 56) achieved complete response (CR) or stringent complete response (sCR). Poorer outcomes were observed in patients with triple exposure, high cytogenetic risk, or failure to achieve CR. Better outcomes were associated with a CAR-T cell persistence of at least six months and sustained MRD negativity. Prolonged MRD negativity was strongly correlated with longer progression-free survival (PFS), with median PFS durations of 58 months, 64 months, and not reached (NR) for patients who maintained MRD negativity for 12, 24, and 36 months, respectively. Patients who remained MRD-negative and progression-free exhibited higher CAR-T cell expansion peaks. Additionally, CAR-T cell persistence was positively correlated with the duration of MRD negativity duration, PFS, and overall survival (OS). Conclusions BCMA CAR-T therapy provides durable responses in a subset of patients with r/r MM. Early intervention may improve patient prognosis by promoting sustained MRD negativity, thus improving overall treatment outcomes. Trial registration Trial registration Chinese Clinical Trial Registry, ChiCTR2000033946 ( https://www.chictr.org.cn/showproj.html?proj=53503 ), Registered June 18, 2020. Trial registration Chinese Clinical Trial Registry, ChiCTR1800018137 ( https://www.chictr.org.cn/showproj.html?proj=30653 ), Registered August 31, 2018.